Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
Pancreatic cancer is the 4th leading cause of cancer deaths in the US and carries the worst prognosis. Ninety-five percent of all pancreatic tumors are adenocarcinomas. Less than 4% of diagnosed patients have 5 year survival or better, with a median survival of only 3 to 6 months.
Generally speaking, pancreatic cancers are notoriously insensitive to the backbone of cancer chemo- and radiation therapy, all of which target processes essential for genome maintenance. Pancreatic adenocarcinomas are highly resistant to conventional chemotherapies and are a major obstacle to improving treatment outcomes. Gemcitabine is a cytotoxic drug that is the first-line therapy for patients with metastatic pancreas cancer because of a modest improvement in survival over other drugs. Gemcitabine, a nucleoside analog that blocks DNA replication, remains the first line therapy for patients with advanced pancreatic cancer. Even with treatment, however, most patients will not survive more than one year.
While early diagnosis will significantly improve treatment options, efforts to enhance chemosensitivity of tumors are equally important. Novel treatment strategies are especially needed given that Phase III trials of various cytotoxic agents in combination with gemcitabine did not show improvement over gemcitabine alone (Van Cutsem E et al. (2004) J. Clin. Oncol. 22:1430-8; Philip P A (2009) J. Clin. Oncol. 27:5660-9; Moore M J (2005) Semin. Oncol. 32:5-6).